The present invention relates to solid-state montelukast, pharmaceutical compositions comprising the same, as well as to processes of making and using the same.
Montelukast, chemically [R-(E)]-1-[[[1-[3-[2-(7-chloro-2-quinolinyl)ethenyl]phenyl]-3-[2-(1-hydroxy-1-methylethyl)phenyl]propyl]thio]methyl]cyclopropane acetic acid, has the following structure of formula (1):

Montelukast monosodium salt (montelukast sodium) is commonly used for treatment of asthma. It is marketed under the brand name SINGULAIR® (Merck) in the form of oral tablets, chewable tablets, and granules. The structure of montelukast sodium corresponds to formula (2):
wherein M+ represents a sodium cation. Montelukast sodium is a hygroscopic, white to off-white powder that is freely soluble in ethanol, methanol, and water and practically insoluble in acetonitrile.
Although several patents relate to montelukast and related compounds, no patent shows the isolation, crystallization or precipitation of solid montelukast, that is the acid, but rather only a salt of montelukast is shown to be obtained in solid state. For example, U.S. Pat. No. 5,565,473 to BELLEY et al. (see also corresponding EP 0 480 717) discloses a genus of pharmaceutically useful compounds that encompasses montelukast and salts thereof. Example 161 of BELLEY et al. purports to make the sodium salt of montelukast via the free acid. However, neither the formation of the free acid, nor the salt, is shown in detail. Instead, the remainder of the synthesis is stated to be carried out under the procedure of steps 10-12 of Example 146. According to Example 146, the (analogous) acid is not rendered or isolated in a solid form but rather the acid remains in an oil form and/or in solution. Only the sodium salt is isolated in solid state. Thus, BELLEY et al. fails to show obtaining a solid state montelukast.
Similarly, WO 95/18107 discloses methods of preparing, inter alia, montelukast and it salts, but does not disclose montelukast, i.e., the free acid, isolated in solid state. Instead, according to the preferred embodiment, and Example 7, the montelukast is converted in situ to the readily isolatable crystalline dicyclohexylamine salt and then subsequently converted to the sodium salt. According to WO 95/18107 this offers a simple and efficient method for the purification of montelukast and for the preparation of the crystalline montelukast sodium.
A similar disclosure is found in U.S. Pat. No. 5,523,477 to KING et al. Example 2 shows the formation of montelukast and conversion into the dicyclohexylamine salt, which is then precipitated. Example 3 shows the conversion of the montelukast dicyclohexylamine salt to sodium montelukast by dissolving the solid dicyclohexylamine salt in toluene and adding acetic acid to reform the free acid. Then to the organic layer containing the acid (montelukast) was added NaOH. Solid state montelukast is not reported to be formed.
While the known montelukast sodium is isolatable in solid state, it suffers from various disadvantages. It is hygroscopic and easily absorbs up to 3 equivalents of water. It is also not stable in aqueous solutions as a precipitate may be formed after certain time. In such solutions it is surface active i.e., its behavior resembles a soap, which can cause problems in granulation processes for making tablets. It would be desirable to have a pharmaceutically active form of montelukast that can be easily obtained in solid form and preferably having some improvement over the known sodium montelukast.